BACKGROUND: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.
Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score / Carbone M1, Nardi A2, Flack S3, Carpino G4, Varvaropoulou N3, Gavrila C5, Spicer A3, Badrock J3, Bernuzzi F6, Cardinale V7, Ainsworth HF8, Heneghan MA9, Thorburn D10, Bathgate A11, Jones R12, Neuberger JM13, Battezzati PM14, Zuin M14, Taylor-Robinson S15, Donato MF16, Kirby J17, Mitchell-Thain R18, Floreani A19, Sampaziotis F20, Muratori L21, Alvaro D7, Marzioni M22, Miele L23, Marra F24, Giannini E25, Gaudio E26, Ronca V14, Bonato G6, Cristoferi L6, Malinverno F6, Gerussi A6, Stocken DD8, Cordell HJ27, Hirschfield GM28, Alexander GJ29, Sandford RN3, Jones DE30, Invernizzi P6, Mells GF3, Thomas C, Rahman M, Yapp T, Lye Ch'ng C, Harrison M, Sturgess R, Galaska R, Healey C, Whiteman J, Czaijkowski M, Gray C, Gunasekera A, Gyawli P, Premchand P, Mann S, Elliott K, Kapur K, Watson A, Foster G, Trembling P, Subhani J, Harvey R, McCorry R, Adgey C, Hobson L, Mulvaney-Jones C, Evans R, Mathialahan T, Ramanaden D, Gasem J, Van Duyvenvoorde G, Shorrock C, Seward K, Southern P, Tibble J, Penn R, Gorard D, Maiden J, Damant R, Palegwala A, Jones S, Alexander G, Mells G, Sandford R, Whiteman J, Dolwani S, Prince M, Silvestre V, Foxton M, Dungca E, Mitchison H, Wheatley N, Gooding I, Doyle H, Karmo M, Kent M, Saksena S, Braim D, Patel M, Lord S, Ede R, Paton A, Austin A, Lancaster N, Sayer J, Gibbins A, Hogben K, Hovell C, Fisher N, Carter M, Koss K, Musselwhite J, Muscariu F, Piotreowicz A, McKay A, Grimley C, Neal D, Ting Tan L, Lim G, Brighton J, Foale C, Ala A, Saeed A, Flahive K, Wood G, Townshend P, Ford C, Brown J, Kordula J, Bowles J, Wilkinson M, Palmer C, Ramage J, Gordon H, Featherstone J, Ridpath J, Ngatchu T, Levi S, Shaukat S, Sadeghian J, Shidrawi R, Williams B, Abouda G, Jones S, Duggan C, Hynes A, Narain M, Rees I, Salam I, Crossey M, Taylor-Robinson S, Brown A, MacNicol C, Williams S, Wilhelmsen E, Banim P, Raymode P, Chilton A, Das D, Lee HJ, Curtis H, Heneghan M, Gess M, Durant E, Drake IM, Bishop R, Davies M, Jones R, Aldersley M, Ncube N, McNair A, Srirajaskanthan R, Sen S, Casey R, Bird G, Mendall M, Cowley C, Barnardo A, Kitchen P, Yoong K, Amore K, Sirdefield D, Orpe J, Mathew R, MacFaul G, Wrigth A, Shah A, Evans C, Keggans J, Bird B, Baxter G, Saha S, Pollock K, Hughes M, Bramley P, Grieve E, Young K, Fraser A, Mukhopadhya A, Ocker K, Mills P, Hines F, Shallcross C, Wilkins J, Grellier L, Campbell S, Martin K, Bathgate A, Innes C, Shepherd A, Rushbrook S, Valliani T, Przemioslo R, Fairlamb H, Macdonald C, Eastick A, Metcalf J, Tanqueray E, Shmueli U, Holbrook B, Davis A, Browning J, Naqvi A, Walker K, Lee T, Verheyden J, Slininger S, Ryder SD, Chapman R, Collier J, O'Donnell D, Stafford L, Williamson K, Kent L, Klass H, Ninkovic M, March L, Cramp M, Simpson D, Dickson C, Sharer N, Hayes M, Goggin P, Quinne M, Pearson S, Hoeroldt B, Jones L, Wright A, Booth J, Loftus A, Lipscomb G, Dewhurst H, Gunter E, Williams E, Fouracres A, Farrington L, Graves L, Hussaini H, Stableforth B, Marriott S, Ayres R, Leoni M, Burroughs A, Marshall E, Thorburn D, Tyrer D, Martin K, Lombard M, Patanwala I, Dali-Kemmery L, Lambourne V, Maltby J, Vyas S, Colley J, Shinder B, Singhal S, Jones J, Mills M, Gleeson D, Carnahan M, Butterworth J, Boulton K, Taylor N, George K, Harding T, Tregonning J, Douglass A, Brown C, Clifford G, Panter S, Gocher D, Shearman J, Bray G, Hamilton M, Butcher G, Forton D, Mclindon J, Curtis J, Das D, Shewan T, Cowan M, Whatley G, Nasseri M, Grover B, Sivaramakrishnan N, Ducker S, Houghton K, Jones D, Griffiths L, Tripoli S, Pitcher M, Shpuza E, White N, Ghosh D, Douds A, Green M, Brookes M, Cumlat L, Wong VS, Warner K, Netherton K, Mandal A, Jain S, Gupta H, Sanghi P, Pereira S, Neuberger J, Gunson B, Hirschfield G, Lim RT, Gallagher S, Clement D, Brind A, Watts G, Mupudzi M, Wright M, Gitahi J, Gordon F, Gocher D, Unitt E, Pateman H, Batham S, Delahooke T, Grant A, Conder J, Higham A, Cox M, O'Donohoe L, Currie L, King A, Oblak M, Collins C, Whalley S, Quinn M, Baird Y, Amey I, Fraser J, Li A, Cotterill D, Bell A, Watson A, Singhal A, Gee I, Greer S, Ang Y, Ransford R, Allison J, Gotto J, Dyer S, Sweeting H, Millson C, Invernizzi P, Carbone M, Cristoferi L, Bonato G, Malinverno F, Bernuzzi F, Alvaro D, Labbadia G, Bragazzi MC, Andreone P, Muratori L, Azzaroli F, Floreani A, Galli A, Tarocchi M, Giannini E, Miele L, Gasbarrini A, Grieco A, Marrone G, Donato MF, Valenti L, Marra F, Marzioni M, Maroni L, Rigamonti C, Zuin M, Battezzati PM, Picciotto A.. - In: THE LANCET. GASTROENTEROLOGY & HEPATOLOGY. - ISSN 2468-1253. - ELETTRONICO. - 3:(2018), pp. 626-634. [10.1016/S2468-1253(18)30163-8]
Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score
Galli AMembro del Collaboration Group
;Tarocchi MMembro del Collaboration Group
;Marra F;
2018
Abstract
BACKGROUND: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. METHODS: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. FINDINGS: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). INTERPRETATION: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.
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